Hydroxy aromatic carboxylate-resin adsorption composition



United States Patent 9 M HYDROXY ARQMATIC' CARBOXYLATE-RESIN. ABSORPTION COMPOSITION Edwin L. Gustus, Chicago, Ill;

NO Drawing. Application January 22,. 1 95 1;. Serial N0..207,225'

8- Claims. (Cl. 167-65) The invention relates to medicinal compositions and includes adsorption compounds of hydroxy mononuclear aromatic. carboxylic' acids, preferably mixed. with compoundsof succinic acid, particularly an. adsorption compound thereof.

For many years the most satisfactory treatment agents for the mild and moderately severe. cases of rheumatoid arthritis have been based on salicylates or on derivatives of salicylic acid. Sodiumand. calcium salicylate, acetylsalicylic acid and its salts, salicylrsa'licylate and salicylamid have been the more common forms in which the salicylic acid radicalhas been given.

A severe disadvantage of the use of; treatment" agents containing salicylic; acid or its compounds has been the need for-rather large dosages in order to obtain a satisfac tory'reli'ef of symptoms. Such large dosages as are necessary to be effective frequently produce symptoms of saiicyli'sm or saiicylate intoxication. Other'und'esiredef fects are also observed. such as irritationof the stomach with consequent gastric distress. This is particularly disturbingto those suffering from gastro-duo'denal'ul'cers;or tlitose with an, ulcerdiathesis and a previous history of' u cers;

More recently it was observedthat. when a: salicylate is given to human subjects a. portion of it is changed to gentisic acid among other products. This suggested that gentistic acid and gcntisates might also show the therapeutic property exhibited by salicylates and ledcto. a trial of the salts of gentisic acid in cases ofrheumatoid'arthri tis.

As a result-of these studies it'was observed that gentisic acid and gentisates possessed the therapeutic activity toward rheumatoid arthritis which had been Observed. with salicylates. It was found, however, that gentisates had to be administered in rather large dosages,,10'to 26 grams daily being the usual dose. Thelatter dosage was given in severe rheumatic attacks at, the start of therapy and after the attack was under control dosages ofthev order. of 1'0 grams a day were. recommended. for maintenance. It was also noted that. gentisic acid and gentisates given orally are rapidly absorbed and then rapidly eliminated from the blood streamby means of the kidneys- For, this reason large total" dosages were given, since the rapid absorption and. elimination operated to, decreasethe efiectiveness ofthedrug. A great, many compounds and derivatives of'gentisic acid were, preparedby various investigators in, the hope of finding, some form. in which genti'si'c acid. could, be. administered which Would not, be so rapidly eliminated from the bloodstream and hence would have a, more prolonged action, requiring; less, total dosage f the, drug;

An Object. of the, invention, istheprovision offcomposi: tions containing a derivative. of hydroxy mononuclear aromatic. carboxylicacids, such-as gentisic acid and} salicylic acid; which, havev a prolonged, action-andrequireless total. dosageofj the drug,

A further objectof this inventionis the provision, of new. compounds and compositions. for. the treatment, of. rheumatoid arthritis at a. cost considerablyless than that. of cortisone.

These and. other objects areaccomplishedby combining, an anti-arthritic hydroxy mononuclear aromatic carlioxylicacid', including gentisic acid;(.2;5Edihydroxybenzoic acid). liomogent-isi'c. acidi (2.,5dihydroxyphcnylacetic. an and. salicylic. acitih, with: an acid adsorbing resin. lilctleasedefiectiveness, is, attainedby mixing the adsorp,- tion. compound? with. a succinate, and" particularly, with.

2,697,059 Patented Dec. 14, 1954 an acid adsorbing resinihavingadsorbed thereon thezanion of a succinicv acid, i; e. the free acid or a monoester thereof. There appears to be asyner-gistic action between these two drugs, bothuseful in thetreatment of rheumatoid arthritis, which makes the mixture,- more efiective than eitherdrug alone in comparable dosage. Of course,.mixtures of an adsorption compound: oii resin and one hydroxy mononucelar aromaticcar-boxylic acid. and. at least one other adsorption compound of resin and. another hydrox-y mononuclear aromatic carboxylic acid: can: be used alone or mixed with a. succinate or with other ma, terials: with or without the succinatm. For example; a: mixture of the adsorption compound ofiresin and gentisicacid and the adsorption. compound of. resinand; salicylic; acid canbe used. I

The. term hydroxy mononuclear. aromatic carboxylic acids as used herein, includes derivatives, in which there: is substitution of the hydrogen of the hydroxy' groupnor' the. hydroxy groups. For example, the term includes, the acetyl derivatives, such as acetylsalicylic acid, An, other type,- of substitution; is lowerj'alkyl, e. g.,- methyl: and ethyl, ether ofthehydroxy carboxylic acid. An eX.-- ample is the dimethyl ether of; homogentisic. acid", i. e., 2,ivdimethoxyphenylacetic aciid, and the: adsorption com: poundiof itand? the resin-hasbeenprepared.

Theresin adsorption compounds ofthis invention are made by contacting an acid; adsorbing resins (commonly called an anion exchange resin);- with: the desired: acid The preferred product isobtained by reacting a. weak: base acid adsorbing. resin, such; as: a polyaminer resin, having secondary ortertiary amino groups, wit-h' the organic carinoxylic acid. This reaction may be represented as fol;-

ows:

wherein RCOOH represents the hydroxy; mononuclear arc: matic carboxyl'ic acid, and. in, thecase of the. succinate adsorption. compound,,to beusedi with; the other adsorption. compound, RCOlOI-I represents s'uccinic acid. or a mono ester. of succini'cacid.

Another formof'the complex whichisalso efiective, but: in which the actual drug portionis more strongly bound,.is.- obtained by reacting; av strong: base, acid. adsorbing. resin, such. as. a. quaternary ammonium. anion exchange resin, with either the, organic, carboxylicacid or its. salts. This reaction. may berepresented. for the salt. of the organic. carboxylic acid as follows:

In.theaboveequationzA. represents a resin: nucleus, such as; a polyamine+aldehyde or polyamine-ketone condensation product having amino or imino or tertiary amino groups: represented by- NH2', -NRR" where R. represents an aliphatic, ali'cyclic; aromatic or alkaryl' residue and: M: represents. a metal or ammonium ion.

Another fOlml of the complex or adsorptioni compoundiresults fromthe use'ofianion-exchange resins Whichhave been. treated with a dilute solutionof a soluble aluminum. saltsuch. as, for' example, aluminum sulfate. Such products are included in the term acid adsorbing resins. V

The term acid adsorbing--resins "as' used in this specification is to be understood as including what: are com monly'called anion exchangeresins, thus covering resinscontaining not attachedt anion, those infree baseform, and those which contain an. anion of a weak acid. Acid adsorbing resins which can be utilized in the present ina1ip'hatioi primary;, secondary on tertiary amino groups,

.01: the quaternary ammonium. group. structures. They can be amine aldehyde or amine ketone condensation products. Such amine resins are referred to in this specification as polyamine acid adsorbing resins. One type of acid adsorbing resin which has given satisfactory results is sold by Rohm and Haas Co. under the trade name XE-58. This is a weak base polyamine anion exchange resin. More particularly it is a polyethylene polyamine methylene substituted resin of diphenylol dimethyl methane and formaldehyde. The polyamine acid adsorbing resins disclosed in United States Patent 2,402,384 have also been highly satisfactory.

In addition to the particular type of polyamine aldehyde resin used in the examples cited here, other acid adsorbing resins can be used provided, of course, that they have sufiicient adsorbing capacity for the carboxylic acids used in preparing the compositions of this invention and are physiologically innocuous. For example, a metaphenylene diamine-formaldehyde acid adsorbing resin could have been used although its adsorbing capacity is somewhat lower than that of the resin given in the examples. Still other acid adsorbing resins can be employed, such as acid adsorbing resins prepared from amines and polysaccharides, ethanolamine alkyd resins, alkylated aromatic diamines, and aromatic diamines both unmodified and modified by incorporating into the resin molecular structure during preparation alkyl groups to form quaternary ammonium bases. Also amine resins co-condensed with aliphatic polyamines or with polyimines can be used, or amine resins treated during preparation with cyanarnide or with dicyandiamide, thus in- I troducing the strongly basic guanidino group. Acid adsorbing resins prepared by reacting aliphatic polyamines with polyhalogen derivatives of hydrocarbons can be used, as well as acid adsorbing modified phenolic resins. innocuous or inert and should be sparingly soluble or in soluble in water and in dilute acids or bases.

The compositions of this invention can be used as such, which is in substantially moisture-free form, or they can be intermixed with other pharmaceutically compatible ingredients or excipients. For example, it may he desired to give it in capsules, pills, tablets, or as a powder, or even in syrups, elixirs, or emulsions. They can be intermixed with flavoring and coloring materials, clay, bentonite, antacids such as magnesium or aluminum oxide, aluminum phosphates, basic aluminum amino acefate and analogues and the like or bismuth suboxide, or bismuth or zirconium subcarbonates, emollients such as methyl cellulose, gastric mucin, carboxy methyl cellulose,

sodium carboxy methyl cellulose, sulfated gluten and the i like, or with naturally occurring gums and mucilages, gelatin, amino acids and their salts, peptones, peptides, or with any other ingredients cooperative therewith or not incompatible therewith.

The following examples illustrate the invention. amples I, III and IV illustrate the complexes which are used in the compositions of the present invention, while Examples II and V illustrate the succinate complexes or adsorption compounds which are used with the complexes of hydroxy mononuclear aromatic carboxylic acids in a preferred embodiment. Examples VI through VIII illustrate the complexes or adsorption compounds which can be mixed with the complexes of hydroxy aromatic carboxylic acids of this invention in other embodiments thereof.

In all of these examples the acid adsorbing resin used was XE58 resin in finely powdered form and in free base form. The resin contained 2% moisture, removable by heating to 50 C. and maintaining at 50 C. until a constant weight was attained. In Examples I, II, VI, VII and VIII the resin was used without drying. In the other examples, the resin was heated at 50 C. to constant weight before use. In all examples, the weight of resin is stated on a dry basis. It will be evident from these examples that drying the resin, before use in the preparation of the adsorption compounds, is unnecessary. Of course, the same process can be used when making adsorption compounds using other acid adsorbing resins.

EXAMPLE I Saturated complex of acid adsorbing resin and gentisic acid 264 grams of XE-58 resin were placed in a glass vessel and 1000 ml. of distilled water were added. After stlrrmg well, a slurry of thoroughly Wetted resin powder In all cases, the resin should be physiologically l.

in water resulted. To this were added with stirring 317 grams of gentisic acid, C. P. anhydrous. This was added in portions, although the entire amount can be added at one time. The suspension was allowed to stand at room temperature for two to three days with occasional stirring. The suspended saturated complex of the polyamine acid adsorbing resin and gentisic acid was then filtered off by suction and the cake was washed three successive times with approximately its own volume of distilled water, sucking the wash liquor down well each time.

The damp cake was broken up and air dried at room temperature and was then dried in air to constant weight at 4850 C. The resulting product weighed 554 grams and contained 53.1% gentisic acid and 46.9% resin. The filtrate and wash liquors were found to contain about 27 grams of gentisic acid which has been present as a slight excess. The dry powder was slightly more orange colored than the original resin. It was pulverized and sifted through an 80 mesh screen and it was then ready for use. The product kept well at room temperature and was sparingly soluble in water. Some degree of hydrolysis occurred when the material was shaken up with distilled water and an acid solution resulted containing gentisic acid in small amounts.

EXAMPLE II Saturated complex of acid adsorbing resin and succinic acid 200 grams XE-58 resin were added to 1000 ml. of distilled water in a glass vessel and stirred until a smooth, thoroughly wetted slurry resulted. 200 grams of C. P. succinic acid crystals were added with stirring over a four hour period. The mixture was allowed to stand at room temperature for three days with frequent stirring. The suspended saturated complex of polyamine resin and succinic acid was filtered off and Washed by suction three times, using each time a volume of distilled water approximately equal to the volume of the moist cake of resin complex. The cake was broken up and dried in air at room temperature and then at 48-50 C. to constant weight. The dried product weighed 329 grams and contained 40.5% succinic acid and 59.5% resin. The mother liquor was found to contain 71 grams of unreacted succinic acid. This solution is suitable for inclusion in a subsequent preparation in place of a corresponding amount of water and of succinic acid. The product was powdered and sifted through an 80 mesh screen before use. On placing some of the practically insoluble product in water and shaking, the water became acid due to some hydrolytic cleavage of the saturated resin complex.

Following the preparation of the gentisic acid complex mentioned above it was put up into capsules and tried on patients with mild to moderate rheumatoid arthritis. It was found that very considerable and satisfactory relief was obtained when two or three capsules each containing 350 mg. of the saturated complex (52% gentisic acid) were taken at five intervals during the day. A great decrease in the swelling around the involved joints was observed in a short time and the amount of movement possible in the joint was considerably increased. The patient observed that the amount of urine voided was increased and this was compatible with the reduction of the swelling around the joints which was due to edema.

Since the total quantity of gentisic acid taken in one day, using the gentisic acid-resin complex, was of the order 1.75 grams to 2.8 grams, it was easily seen that this was far below the lowest dosage reported for sodium gentisate in effective dosage (5 grams per day) and very much less than the more customary dosages of this salt, namely, 15-26 grams per day used in severe cases.

A product was then made by mixing together the pulverized resin complex of gentisic acid with the similar product containing succinic acid, and this mixture was found to give excellent therapeutic results at still lower total dosages of gentisic acid. In this case the product was prepared by mixing 35 grams of a gentisic acid-resin complex containing 54.5% gentisic acid and 33.6 grams of succinic acid resin-complex containing 39.75% succinic acid. The mixture then contained 19.1 grams of gentisic acid and 13.38 grams of succinic acid on a total weight of the mixed resin complexes of 68.6 grams. The mixture contained, therefore, 27.9% gentisic acid and 22.8% succinic acid. It was put up in capsules each containing 343 mg. Each capsule, therefore, represented 95.8 mg. gentisic acid and 74.8 mg. of succinic acid. This preparation was effective in a moderateeasetaft dosages of 's'ix to ten capsules a day, representing .a total'dosage of 575 il'llg. to 958 mg. of gen-tisi'c acid per day. It'fis obvious that this preparation represented {a great advance in the therapeutic approach to rheumatoid arthritis on a symptomatic basis, and it may be mentioned here thatfthere is no other type of therapy ithan symptomatic treatment known for this-disease at=- resent.

In this embo iment using adsorption compounds of hydroxy mononuclear aromatic carb'oxyl-ic acid, sudh as gentisic acid, and of succinic acid, it is preferred that the aromatic carbox-ylic anion content and the gsuccinicacid anion content be approximately 'equah-although'widevariation in the ratio canb'e made.

EXAMPLE I-II Saturated complex of acid adsorbing resin and salicylic -:a'cid grams of XE SS resin and 2J7 grams of salicylic acid wereaddedto 800 ml. ofdistilledtwateniandthe mixture was stirred at room temperature for fourthours. The suspension was filtered on a suction funnel and the clear filtrate was strongly acid and contained salicylic acid. The resin salicylic acid -adsorlption icomplex, retained on the suction funnel, was freed from uncomhincdsalicylic acid by -thr-ice repeated gravity washing with 100 ml. por- Lions of acetone, in which free salicylicia'cid,issvery-soluble. Fllhe final portions of the :third acetone wash Wcrcremoved by suction and the resin-salicylic acid adsorption soomplex was dried in air at 50 C. It weighed 42.42 gramsand contained 37.8% of salicylic acid:and:.62.2% resin.

EXAMPLE IIV Saturated complex 0.7 :acid lazso-nbing resin and salicylic 280 grams of XE- 58 resin were added to 2000 ml. of distilled water in a five liter flask. The mixture was agitated until a smooth suspension resulted and the resin was thoroughly soaked. This required about an hour. 315 grams of powdered salicylic acid, C. 'P., were added and the mixture was agitated until ,a smooth mixture resulted. The flask and contents were allowed to stand at -45 C. for four to fine days with requent shaking. The contents of the flask were then collected on a suction funnel and the clear filtrate after warming to 40-45" C. was re'filtered through the cake in the funnel. This process of warming the filtrate and refiltering it through the cake was repeated eight times and the final filtrate, which was slightly acid, was discarded.

The damp cake was freed from mother liquor as much as possible by pressure and suction. The cake 'Was then given three washes using each time about one-half its volume of C. P. acetone. The acetone removedwater and any free salicylic acid. The final acetone wash was sucked from the well pressed cake, as far as possible, and the cake was broken up as finely as possible and dried in air at room tern erature and finally in air at C. until constant in we'i'g' t. The product weighed 575 grams and consisted of 280 grams of resin on which was adsorbed 296 grams of salicylic acid; thus, the product contained 51.6% salicylic acid and 48.4% resin.

A comparison of Examples III and IV shows that a greater amount of acid adsorption is obtained by saturation at a higher temperature.

Modifications to a gentisate-succinate-resin preparation for rheumatoid arthritis In the case of the resin complex of succinic acid the product has a very acid reaction in the stomach, probably due to the fact that a large portion of the adsorbed succinic acid molecules are attached to the resin by only one carboxyl group. This leaves a carboxyl group free and available for ionization of hydrogen ions. Consequently, it is advisable to butter the succinic acid-adsorption complex with an appropriate buffer, e. g., a phosphate buffer mixture in any final pharmaceutical product.

The composition containing the complex of the resin and succinic acid can be used as an enteric coated form so that the tablet or capsule would not open in the stomach but would open in the intestinal tract. A coating of salol is suitable therefor.

Another procedure is that of substituting for the resinsuccinic acid adsorption complex, as described, a saturated complex of the resin with a monoester of succinic acid,

6 8 t fl yl estercit succinic acid. A resin:eomplex of the monobenzyl succinate would yield on hydroly' sis monobenzyl ester of succinic acid which is apparently as active as is succinic acid. Further hydrolysis in thej'alimentary tract gives benzyl alcohol :and succinic acid or sodium *succ'ina te. Elns'tead 0f the monobenzyl ester of succinic acid, a lower alkyl, "such as ethyl, rnonoester of succinic acid can be used, preferably as the adsorption compounded with t he a'oid adsorbing resin.

Saturated complex ofacid adsorbing resina-nd monobenzyl ester of succiniczacid 50 grams of XE 58' resin were stirred up with enough distilled water to make a thin slurry, and this was allowed to stand with occasional stirring for one hour. The well soaked resin powder wasfiltered bysuction and washed several times by suction with small amounts of distilled water, and the cake was sucked down well to remove most of the mechan'icallyh'eld water.

The damp resin cake was transferred quantitatively to a one li ter beaker, washing in the last tra'ces with 'a' little distilled water. Fifty grams of monobenzyl ester of succinic acid were rubbed up in suflicient distilled water to give a slurry tree of lamps and as finely divided as possible, and this was then washed into the beaker containing the resin. 'Dstilled water was then added until the beaker was about 69% full and the resin and monobenzyl ester of succinic acid were stirred to give a smooth suspension. The beaker and contents were placed in -a warm area so that the temperature of who suspension reached 4045" C. and was allowed to stand -'at "this temperature with frequent stirring for forty-eight hours. The supernatant liquor should be acid to litmus paper but not to Congo paper at this point. t

The saturated resin complex was filtered ull? by suction and washed twice with a volume of distilled water approxirrrately'that of thee-eke. The cake was then washed three times with portions of isopropyl alcohol, each portion approximately one-half the volume of the cake and each wash being rcrno ed by suction before adding the following wash. ,the washed cake was dried in air at room temperate-ire and then at 50 until constant in Weight. The product Weighed 9'5 grams and contained 50 grams of resin to which was adsorbed '45 grams of monobenzyl ester of succinic acid. It contained, therefore, 4 7.45% monobenzyl ester of succinic acid and '52;-5'5% res-in.

Also it should be kept in mind that a final pharmaceut-ioal preparation for rheumatoid arthritis can contain, besides the complex of resin and hydroxy mononucl-ear aromatic oarboxylic acid, such as gentis'ic acid, alone or with a succi-nate, preferably a complex "of succinic acid, drugs like ascorbic acid, para-aminobenzoic acid and nicotinic "acid. These drugs could be added as such or as their complexes with resins. Since such complexes are new, the preparation 'otthem will be described.

EXAMPLE VI Saturated complex of acid adsorbing resin and ascorbic acid 20 grams of XE-58 resin wereplaced in a glass container with the 20 grams of ascorbic acid crystals. While stirring the powder, 300 ml. of distilled water were added. A smooth slurry resulted.

The suspension was allowed to stand for fourteen hours with frequent stirring. The saturated resin complex with ascorbic acid was then filtered off by suction and washed three times, using each time a volume of distilled water approximately equal to the volume of the resin-complex cake. The product was then dried in an atmosphere of nitrogen at room temperature at subatmospheric pressure to constant weight. The dried product Weighed 38.4 grams and contained 48% adsorbed ascorbic acid and 52% resin.

EXAMPLE VII Saturated complex of acid adsorbing resin and para-aminobenzoic acid 13 grams of para-aminobenzoic acid were dissolved in ml. of methyl alcohol and then 125 ml. of distilled water at 50 C. were stirred in. The warm solution was decanted from any traces of manufacturing debris and to the clear solution 10 grams of XE-58 resin suspended in 100 ml. of 50% by volume methyl alcohol were added with stirring. The suspension was allowed to stand for three days at room temperature with occasional stirring.

The saturated complex of XE-58 resin and paraaminobenzoic acid was collected on a suction filter. The filtrate was quite acid, showing that an excess of paraaminobenzoic acid had been used. The filter cake was washed four times by gravity, using each time a volume of methyl alcohol equal to the volume of the cake. The cake was finally sucked down well and dried at room temperature in air, then to constant weight at 50 C. The product weighted 17.5 grams and contained 43% adsorbed para-aminobenzoic acid and 57% resin.

EXAMPLE VIII Saturated complex of acid adsorbing resin and nicotinic acid 35 grams of XE-58 resin powder were added with stirring to 1500 m. of distilled water at 40 C., in which were dissolved 30 grams of nicotinic acid. The suspension was then allowed to stand at 40 C. for three hours with frequent stirring, and then for about twelve hours at room temperature with occasional stirring. The saturated resinnicotinic acid complex. was collected by suction on a Buchner funnel and was sucked free as possible of aqueous liquor. The filtrate was acid to litmus paper and containced nicotinic acid, assuring that an excess had been use The resin-nicotinic acid complex cake was washed three times, using each time a volume of distilled water approximately equal to that of the cake. The distilled water was warmed to 40 C. The wash water was removed from the cake as far as possible by suction and the cake was crumbled and dried in air, first at room temperature and finally to constant weight at 50 C. The final product weighed 53.94 grams and contained 36.5% nicotinic acid and 63.5% resin. The acid filtrate containing the excess nicotinic acid could be used to replace nicotinic acid and water in a subsequent preparation.

While the foregoing examples illustrate the preparation of adsorption compounds of hydroxy mononuclear aromatic carboxylic acid in which the acid adsorbing resin is saturated with such acids, the present invention is not limited to the use of resins saturated either at room temperature or at elevated temperature with these carboxylic acids. The same is true with regard to succinate adsorbed on an acid adsorbing resin when the latter is to be used with the adsorption compounds of hydroxy mononuclear aromatic carboxylic acids. Similarly, resin complexes of other materials such as used in Examples VI through VIII need not have the resin saturated with such matrials. It is preferred, however, that the resin be saturated with the anion of hydroxy mononuclear aromaic carboxylic acid, succinate, or the other material, where the succinate or other material is used as the complex.

The adsorption compounds and compositions of this invention are also useful in the treatment of rheumatic fever. Particularly efiective results in the treatment of rheumatic fever are obtained by administering to the patient an acid adsorbing resin having adsorbed there on 3-hydroxy-2-phenyl-cinchoninic acid.

While I have described certain preferred embodiments of my invention, many modifications thereof may be made without departing from the spirit of the invention; and I do not wish to be limited to the detailed examples, formulas and proportions of ingredients herein set forth, but desire to avail myself of all changes within the scope of the appended claims.

I claim:

1. A therapeutic composition suitable for the treatment of rheumatoid arthritis comprising a polyamine acid adsorbing resin having adsorbed thereon an anion of an anti-arthritic acid consisting of a benzene nucleus containing a maximum of two hydroxyl groups attached to the nucleus and a carboxyl-containing side chain having a maximum of two carbon atoms, at least one of the nuclear hydroxyl groups of said acid being adjacent to the carboxyl-containing side chain.

2. The composition of claim 1 wherein the acid is gentisic acid.

3. The composition of claim 1 wherein the acid is salicylic acid.

4. The composition of claim 1 wherein the acid is homogentisic acid.

5. A therapeutic composition suitable for the treatment of rheumatoid arthritis composing a weak base polyamine acid adsorbing resin having adsorbed thereon an anion of an anti-arthritic acid consisting of a benzene nucleus containing a maximum of two hydroxyl groups attached to the nucleus and a carboxyl-containing side chain having a maximum of two carbon atoms, at least one of the nuclear hydroxyl groups of said acid being adjacent to the carboxyl-containing side chain.

6. The composition of claim 5 wherein the acid is gentisic acid.

7. The composition of claim 5 wherein the acid is salicylic acid.

8. The composition of claim 5 wherein the acid is homogentisic acid.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,402,384 Eastes June 18, 1946 2,415,558 Hesler Feb. 11, 1947 2,471,394 Gubner May 24, 1949 OTHER REFERENCES Bhatnagar, Journ. of the Indian Chem. Soc., vol. 13 (1936), pp. 679 to 688.

Meyers, Sci., vol. 108, Sept. 10, 1948, p. 281.

Kendall, Chem. & Eng. News, June 19, 1950, vol. 28, pp. 2074 to 2077.

Amberlite, Adsorption of Organic Acids by Amberlite IRA-400, Sept. 1949, pp. 1, 2 and 3.

Journal of the American Pharmaceutical Assn., Practical Pharmacy Ed., vol. 11, June 1950, p. 338. 

1. A THERAPEUTIC COMPOSITION SUITABLE FOR THE TREATMENT OF RHEUMATOID ARTHRITIS COMPRISING A POLYAMINE ACID ADSORBING RESIN HAVING ADSORBED THEREON AN ANOIN OF AN ANTI-ARTHRITIC ACID CONSISTING OF A BENZENE NUCLEUS CONTAINING A MAXIMUM OF TWO HYDROXYL GROUPS ATTACHED TO THE NUCLEUS AND A CARBOXYL-CONTAINING SIDE CHAIN HAVING A MAXIMUM OF TWO CARBON ATOMS, AT LEAST ONE OF THE NUCLEAR HYDROXYL GROUPS OF SAID ACID BEING ADJACENT TO THE CARBOXYL-CONTAINING SIDE CHAIN. 